We have recently defined the surface phenotype of a subset of CD8+ T cells programmed to inhibit the activation and expansion of follicular helper T cells (TFH). These regulatory CD8+ T cells express CD44, CD122 and the inhibitory Ly49 receptor on their surface and a T cell receptor (TCR) that recognizes Qa- 1: peptide complexes expressed by TFH cells. These CD8+ Treg cells, which represent less than 5% of the CD8+ T cell pool, inhibit TFH activity through an IL-15- and perforin-dependent mechanism. The development of collagen-induced arthritis (CIA) is associated with B- and T-lymphocyte responses, production of anti-collagen type II antibodies and collagen-specific T cells. Our preliminary studies of a mouse model of CIA support the hypothesis that enhanced interactions between CD8+ Treg cells and target TFH cells profoundly inhibits disease progression. In this proposal, we further define the interaction between CD8+ Treg and target TFH cells in CIA and a murine model of systemic autoimmunity - B6.-Yaa disease - in an effort to develop strategies that increase the activity of CD8+ Treg and inhibit and/or ameliorate disease development. The experimental approaches outlined below should provide new insights into the role of CD8+ Treg in the regulation of autoimmune diseases and form the basis for new therapeutic approaches to rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and related diseases. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) and spondyloarthritis affect ~3 million Americans. Approximately 1 million Americans are afflicted with SLE and related systemic autoimmune diseases. We have made substantial progress in understanding these autoimmune disorders during the last grant period. We propose to utilize these insights to develop new therapeutic approaches to these disorders using mouse models of RA and SLE.